Throughout this application various publications are referred to in parenthesis. Full citations for these references may be found at the end of the specification preceding the claims. The disclosures of these publications are hereby incorporated by reference in their entireties into the subject application to more fully describe the art to which the subject application pertains.
Reperfusion injury refers to damage to tissue caused when blood supply returns to the tissue after a period of ischemia. Intestinal ischemia can occur in a variety of clinical conditions, including small bowel transplant, superior mesenteric artery occlusion, cardiac insufficiency with associated low flow state, and hemorrhagic shock and necrotizing enterocolitis.
Mesenteric ischemia remains a critical problem, resulting in a mortality as high as 60-80% (1). Multiple organ failure, including acute lung injury (ALI) is a common complication of intestinal ischemia/reperfusion (I/R) injuries and contributes to its high death toll (2). ALI is caused by a systemic inflammatory response due to the release of pro-inflammatory cytokines and bacteria-derived endotoxins from reperfused ischemic tissue (3-6). So far, only a limited number pharmacologic treatment options have been found that provide some benefit in I/R and acute lung injury, most of them targeting inflammatory mediators and oxidative stress pathways (7). A key aspect of I/R injury is the increased occurrence of apoptotic cell death of intestinal and bronchial epithelial cells and of type II alveolar macrophages (2, 8-11). Apoptosis is associated by a marked up-regulation of Fas and Fas-ligand, and the activation of caspase-3 in lung epithelial cells (12, 13). Proinflammatory cytokines like IL-1β or TNF-α seem to play a major role in apoptosis induction involving Bid, Bax upregulation and Bcl-2 downregulation (9, 14, 15).
While balanced apoptosis and phagocytosis maintain normal function, deficient clearance of apoptotic cells after ischemia potentially leads to increased inflammation and impaired tissue repair (16, 17). Apoptotic cells expose phosphatidylserine (PS) that can be recognized by soluble molecules and receptors, thereby enabling their phagocytosis (18). One of these molecules is milk fat globule EGF-factor 8 (MFG-E8), which is crucial for apoptotic cell clearance (19). Hanayama et al. found for example that the effective clearance of apoptotic B-cells in the spleen prevents inadequate pro-inflammatory immune responses and the development of auto-antibodies (20). In a rat sepsis model using cecal ligation and puncture, MFG-E8 is downregulated in spleens and livers. This was associated with impaired apoptotic cell clearance and increased mortality in these animals (21). Similar to sepsis, gut I/R injury is accompanied by a systemic inflammatory response.
Milk fat globule EGF-factor 8 (MFG-E8) is a potent opsonin for the clearance of apoptotic cells and is produced by mononuclear cells of immune competent organs including the spleen and lungs. Ischemia-reperfusion (I/R) injuries of the gut induce apoptosis, severe inflammation, and remote organ damage including acute lung injury (ALI). Whether enhancing apoptotic cell clearance is beneficial under such conditions has been unknown. There is a clear need for improved treatment and prevention of I/R injuries.